This invention relates to a process for preparing "cyclopropyl" amino acids (.gradient.AA), defined as .gradient.-amino acids in which the C.sub..alpha. --C.sub..beta. bond is one side of a cyclopropane ring. These amino acids are useful as enzyme inhibitors and as substitutes for natural amino acids in peptide hormones (regulators of bodily functions) to enhance bioactivity, to stablilize the peptide to cleavage by enzymes and to convert these peptides into enzyme inhibitors.
The only process described in the literature (1)+(2).fwdarw.(3).fwdarw.(4) and related to the disclosed process is the addition of CH.sub.2 N.sub.2 (1, R.sup.1 =R.sup.2 =H) to (2). (I. Bregovec and T. Jakovcic, Monats fur Chemie, 1972 103, 288). The commonly known addition of CH.sub.2 N.sub.2 to unsaturated azlactones (M. Bernabe, et al., Ann de Quimica 1972, 68, 501, 1055; Eur. J. Med. Chem. 1979, 14, 44; Syn. Comm. 1977 191; J. Heterocyclic Chem. 1983, 20, 607; Pages, R. A., Burger, A.; J. Med. Chem., 1966, 9, 766; Awad, W. I. et al. Tetrahedron, 1964, 20, 891) is similar but not the same as the process of the present invention which requires the addition of a substituted diazomethane specifically to a dehydroalanine deriva-tive which must be synthesized for this purpose. The initial product is a 5-substituted pyrazoline which is then converted into the .gradient.AA. In the process described in the literature, the initial product is a 4-substituted pyrazoline. The process of the present invention generates chiral cyclopropyl amino acids directly. This means that, if chirality is present in the dehydroalanine derivative, optically active cyclopropyl amino acids can be prepared directly without the necessity of resolution. This is not possible in the other processes reported.
New stereo specific cyclopropyl amino acids are disclosed. Also new peptides containing at least one stereo specific cyclopropyl amino acid are disclosed. The present invention describes a new process for synthesizing stereo specific cyclopropyl amino acids. Additionally, this new process can be used as part of a process for synthesizing peptides containing at least one stereo specific cyclopropyl amino acid residue. The term "amino acid" is understood to include analogs, derivatives, and congeners of any specific amino acid referred to herein.
It is an object of the present invention to provide new stereo specific cyclopropyl amino acids.
It is a further object to provide new peptides containing at least one stereo specific cyclopropyl amino acid residue.
These and other objects, aspects, and advantages of this invention will become apparent from a consideration of the accompanying specification and claims.